PDF(Pubmed)
Abstract：
BACKGROUND: Methylmalonic acidemia (MMA) is a rare inborn error of propionate metabolism caused by deficiency of the mitochondrial methylmalonyl-CoA mutase (MUT) enzyme. As matter of fact, MMA patients manifest impairment of the primary metabolic network with profound damages that involve several cell components, many of which have not been discovered yet. We employed cellular models and patients-derived fibroblasts to refine and uncover new pathologic mechanisms connected with MUT deficiency through the combination of multi-proteomics and bioinformatics approaches.
RESULTS: Our data show that MUT deficiency is connected with profound proteome dysregulations, revealing molecular actors involved in lysosome and autophagy functioning. To elucidate the effects of defective MUT on lysosomal and autophagy regulation, we analyzed the morphology and functionality of MMA-lysosomes that showed deep alterations, thus corroborating omics data. Lysosomes of MMA cells present as enlarged vacuoles with low degradative capabilities. Notwithstanding, treatment with an anti-propionigenic drug is capable of totally rescuing lysosomal morphology and functional activity in MUT-deficient cells. These results indicate a strict connection between MUT deficiency and lysosomal-autophagy dysfunction, providing promising therapeutic perspectives for MMA.
CONCLUSIONS: Defective homeostatic mechanisms in the regulation of autophagy and lysosome functions have been demonstrated in MUT-deficient cells. Our data prove that MMA triggers such dysfunctions impacting on autophagosome-lysosome fusion and lysosomal activity.
RESULTS: Our data show that MUT deficiency is connected with profound proteome dysregulations, revealing molecular actors involved in lysosome and autophagy functioning. To elucidate the effects of defective MUT on lysosomal and autophagy regulation, we analyzed the morphology and functionality of MMA-lysosomes that showed deep alterations, thus corroborating omics data. Lysosomes of MMA cells present as enlarged vacuoles with low degradative capabilities. Notwithstanding, treatment with an anti-propionigenic drug is capable of totally rescuing lysosomal morphology and functional activity in MUT-deficient cells. These results indicate a strict connection between MUT deficiency and lysosomal-autophagy dysfunction, providing promising therapeutic perspectives for MMA.
CONCLUSIONS: Defective homeostatic mechanisms in the regulation of autophagy and lysosome functions have been demonstrated in MUT-deficient cells. Our data prove that MMA triggers such dysfunctions impacting on autophagosome-lysosome fusion and lysosomal activity.
摘要：
背景：甲基丙二酸血症（MMA）是由线粒体甲基丙二酰辅酶A变位酶（MUT）缺乏引起的一种罕见的先天性丙酸代谢错误。事实上,MMA患者表现出原发性代谢网络的损害，涉及几种细胞成分，其中许多尚未被发现。我们利用细胞模型和患者来源的成纤维细胞，通过多蛋白质组学和生物信息学方法的结合，完善和发现与MUT缺乏相关的新病理机制。
结果：我们的数据表明，MUT缺乏与严重的蛋白质组失调有关，揭示参与溶酶体和自噬功能的分子因子。为了阐明MUT缺陷对溶酶体和自噬调节的影响，我们分析了MMA溶酶体的形态和功能，显示出深度改变，从而证实了组学数据。MMA细胞的溶酶体表现为具有低降解能力的扩大的液泡。尽管如此,用抗丙酸药物治疗能够完全挽救MUT缺陷细胞中的溶酶体形态和功能活性。这些结果表明MUT缺乏与溶酶体-自噬功能障碍之间存在严格的联系，为MMA提供有希望的治疗前景。
结论：在MUT缺陷细胞中已经证明了自噬和溶酶体功能调节中存在缺陷的稳态机制。我们的数据证明MMA触发了影响自噬体-溶酶体融合和溶酶体活性的这种功能障碍。
结果：我们的数据表明，MUT缺乏与严重的蛋白质组失调有关，揭示参与溶酶体和自噬功能的分子因子。为了阐明MUT缺陷对溶酶体和自噬调节的影响，我们分析了MMA溶酶体的形态和功能，显示出深度改变，从而证实了组学数据。MMA细胞的溶酶体表现为具有低降解能力的扩大的液泡。尽管如此,用抗丙酸药物治疗能够完全挽救MUT缺陷细胞中的溶酶体形态和功能活性。这些结果表明MUT缺乏与溶酶体-自噬功能障碍之间存在严格的联系，为MMA提供有希望的治疗前景。
结论：在MUT缺陷细胞中已经证明了自噬和溶酶体功能调节中存在缺陷的稳态机制。我们的数据证明MMA触发了影响自噬体-溶酶体融合和溶酶体活性的这种功能障碍。
